The chronic control of tumor growth by a well-tolerated, oral compound would be desirable in the elderly and in asymptomatic individuals at high risk for cancer. Angiogenesis is recognized as an important determinant in tumor development and progression which is not prominent in normal tissues. Copper depletion has been shown to lead to smaller, largely avascular tumors, in animal models of implanted tumors. However, the large size of the implanted tumors used in previous studies may have prevented the detection of any survival benefit due to copper depletion. We hypothesize that oral Tetrathiomolybdate (TM) , the most potent and safest inhibitor of blood copper known (used in humans with Wilson's disease), will retard the onset and/or slow down the growth of mammary tumors in cancer prone Her2/neu+ transgenic mice by an anti-angiogenic mechanism. Preliminary data from our laboratory indicate that long-term administration of TM is safe and effective in the Her2/neu transgenic mouse in completely preventing the appearance of clinically significant tumors. In this application we propose to study TM's effect on angiogenesis in 3 in vivo models: the Her2/neu transgenic mice, the Dunning's rat prostate cancer model, and implanted lung cancer xenografts in SCID mice. The cells from these models will be used in in vitro experiments to test the hypothesis that TM interferes with VEGF secretion and action and angiogenic chemokine IL-6 and IL-8 function. This work will help uncover the molecular events whereby TM affects signaling of the angiogenic switch in cancer. By defining the molecular basis of TM's inhibition of angiogenesis, this work will help tailor the clinical application of TM in cancer.